Impaired glutamate uptake in the R6 Huntington's disease transgenic mice

Neurobiol Dis. 2001 Oct;8(5):807-21. doi: 10.1006/nbdi.2001.0430.

Abstract

Huntington's disease (HD) is a late-onset neurodegenerative disease for which the mutation is CAG/polyglutamine repeat expansion. The R6 mouse lines expressing the HD mutation develop a movement disorder that is preceded by the formation of neuronal polyglutamine aggregates. The phenotype is likely caused by a widespread neuronal dysfunction, whereas neuronal cell death occurs late and is very selective. We show that a decreased mRNA level of the major astroglial glutamate transporter (GLT1) in the striatum and cortex of these mice is accompanied by a concomitant decrease in glutamate uptake. In contrast, the expression of the glutamate transporters, GLAST and EAAC1, remain unchanged. The mRNA level of the astroglial enzyme glutamine synthetase is also decreased. These changes in expression occur prior to any evidence of neurodegeneration and suggest that a defect in astrocytic glutamate uptake may contribute to the phenotype and neuronal cell death in HD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System X-AG / biosynthesis
  • Amino Acid Transport System X-AG / genetics
  • Animals
  • Aspartic Acid / metabolism
  • Astrocytes / metabolism*
  • Biological Transport
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Cerebral Cortex / metabolism
  • Corpus Striatum / metabolism
  • Crosses, Genetic
  • Disease Models, Animal
  • Excitatory Amino Acid Transporter 1
  • Excitatory Amino Acid Transporter 2 / deficiency
  • Excitatory Amino Acid Transporter 3
  • Glial Fibrillary Acidic Protein / analysis
  • Glutamate Plasma Membrane Transport Proteins
  • Glutamate-Ammonia Ligase / biosynthesis
  • Glutamate-Ammonia Ligase / deficiency
  • Glutamate-Ammonia Ligase / genetics
  • Glutamic Acid / pharmacokinetics*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Models, Neurological
  • Nerve Tissue Proteins / analysis
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / analysis
  • Peptides / analysis
  • Phenotype
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Symporters*

Substances

  • Amino Acid Transport System X-AG
  • Carrier Proteins
  • Excitatory Amino Acid Transporter 1
  • Excitatory Amino Acid Transporter 2
  • Excitatory Amino Acid Transporter 3
  • Glial Fibrillary Acidic Protein
  • Glutamate Plasma Membrane Transport Proteins
  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • RNA, Messenger
  • SLC1A1 protein, human
  • SLC1A3 protein, human
  • Slc1a1 protein, mouse
  • Slc1a3 protein, mouse
  • Symporters
  • polyglutamine
  • Aspartic Acid
  • Glutamic Acid
  • Glutamate-Ammonia Ligase